Glaucoma is a leading cause of blindness that presents a considerable diagnostic challenge. Studies have shown that, in glaucoma, up to half of the retinal nerve fibers can be lost before detection. Our goal is to improve glaucoma diagnosis with new imaging methods that can reveal tissue and cell-level structures in the retinal layers affected by glaucoma. These methods are optical coherence tomography (OCT) and light scattering spectroscopy (LSS). OCT is a novel technology that provides cross-sectional retinal images with micron level resolution, which is not possible with any other non-invasive method. It has been used to measure the peripapillary retinal nerve fiber layer (NFL) thickness. Although NFL thickness correlates well with conventional diagnostic indicators, there is still considerable overlap between glaucomatous and normal eyes. We propose to go beyond NFL thickness measurements and develop OCT -based technology to measure internal NFL properties such as reflectivity, birefringence, and backscattering angular distribution. We will also develop high-speed and ultrahigh resolution OCT to allow direct measurement of the much thinner ganglion cell layer (GCL). LSS can detect the sizes of even finer structures such as cell nuclei by measuring resonant spectral modulation in backscattered light. We propose to use LSS to detect glaucomatous changes in sizes of structural components in the GCL and NFL. Cleveland Clinic Foundation, the lead institution, will build these advanced imaging systems using technologies to be developed at Duke Univ., Case Western Reserve Univ., and Harvard Medical School. Initial instrument validation will use animal models of glaucoma developed at CCF and Bascom Palmer Eye Institute (BPEI). The new instruments will be tested in a 5-year clinical trial at CCF, New England Eye Center, and BPEI. High speed OCT will be used in year 1 with other technologies to be introduced to the clinical trial in years 2-4. The greatest portion of the trial will assess the ability of advanced imaging to predict which ocular hypertensive patients will later develop glaucoma as defined by conventional visual field and optic disc evaluation. If these advanced imaging technologies can predict glaucoma development, then they may allow earlier treatment and prevention of visual loss.